An understanding of the mechanisms of treatments for depression and other chronic neurodegenerative processes is an essential goal. Chronic, recurrent depression involves hippocampal atrophy, which can result from chronic stress. Chronic antidepressant treatment restores neurotrophin (BDNF) expression. During our preliminary funding period, we demonstrated that the enhancement of hippocampai BDNF expression resulting from antidepressant treatment is enhanced and accelerated by exercise. We have found evidence, at the transcriptional level, for overlap and synergy between these two interventions, and have demonstrated, using systemic lesions, receptor blockade and neurotransmitter-selective antidepressants, that the noradrenergic system is essential for the observed BDNF changes. Considering the essential role of BDNF for neuronal maintenance and plasticity, our results suggest that exercise may enhance antidepressant treatment response, and repair neuronal degeneration brought about by stress. We now wish to test the hypothesis that exercise and antidepressant treatment converge upon intracellular signaling pathways associated with neuronal survival and plasticity in the hippocampus. Our preliminary evidence suggests that exercise activates the cell survival-enhancing phosphatidylinositol-3 kinase and nitric oxide signaling pathways, in whole animal and hippocampal cell culture models, we will assess the activation of several signaling molecules along these intracellular pathways, and specifically test their involvement in the enhancement of hippocampal BDNF expression following exercise, antidepressant treatment, and noradrenergic activation. We will also test the involvement of other specific survival-promoting pathways (such as cAMP and calcium-mediated) that can be activated by exercise or antidepressant, and where convergence of these two interventions might be demonstrated. With the currently proposed experiments, we also wish to test the hypothesis that our combined interventions will repair stress-induced impairments in hippocampal function (spatial learning deficits), as well as damage to neuronal cytoarchitecture following stress. Our experiments will yield important information about the intracellular, cooperative mechanisms of improved treatment response resulting from exercise. Knowledge about the mechanisms responsible for the enhancement of antidepressant response will inform the development of novel, more efficacious and rapid treatments.